title: Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow.
abstract: Blood neutrophil homeostasis is essential for successful host defense against invading pathogens. Circulating neutrophil counts are positively regulated by CXCR2 signaling and negatively regulated by the CXCR4-CXCL12 axis. In particular, G-CSF, a known CXCR2 signaler, and plerixafor, a CXCR4 antagonist, have both been shown to correct neutropenia in human patients. G-CSF directly induces neutrophil mobilization from the bone marrow (BM) into the blood, but the mechanisms underlying plerixafor-induced neutrophilia remain poorly defined. Using a combination of intravital multiphoton microscopy, genetically modified mice and novel in vivo homing assays, we demonstrate that G-CSF and plerixafor work through distinct mechanisms. In contrast to G-CSF, CXCR4 inhibition via plerixafor does not result in neutrophil mobilization from the BM. Instead, plerixafor augments the frequency of circulating neutrophils through their release from the marginated pool present in the lung, while simultaneously preventing neutrophil return to the BM. Our study demonstrates for the first time that drastic changes in blood neutrophils can originate from alternative reservoirs other than the BM, while implicating a role for CXCR4-CXCL12 interactions in regulating lung neutrophil margination. Collectively, our data provides valuable insights into the fundamental regulation of neutrophil homeostasis, which may lead to the development of improved treatment regimens for neutropenic patients.
authors.affiliation: Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
authors.forename: Sapna
authors.initials: S
authors.lastname: Devi
authors.forename: Yilin
authors.initials: Y
authors.lastname: Wang
authors.forename: Weng Keong
authors.initials: WK
authors.lastname: Chew
authors.forename: Ronald
authors.initials: R
authors.lastname: Lima
authors.forename: Noelia
authors.initials: N
authors.lastname: A-González
authors.forename: Citra N Z
authors.initials: CN
authors.lastname: Mattar
authors.forename: Shu Zhen
authors.initials: SZ
authors.lastname: Chong
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlitzer
authors.forename: Nadja
authors.initials: N
authors.lastname: Bakocevic
authors.forename: Samantha
authors.initials: S
authors.lastname: Chew
authors.forename: Jo L
authors.initials: JL
authors.lastname: Keeble
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Goh
authors.forename: Jackson L Y
authors.initials: JL
authors.lastname: Li
authors.forename: Maximilien
authors.initials: M
authors.lastname: Evrard
authors.forename: Benoit
authors.initials: B
authors.lastname: Malleret
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.forename: Muzlifah
authors.initials: M
authors.lastname: Haniffa
authors.forename: Suet Mien
authors.initials: SM
authors.lastname: Tan
authors.forename: Jerry K Y
authors.initials: JK
authors.lastname: Chan
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
authors.forename: Andrés
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.forename: Lai Guan
authors.initials: LG
authors.lastname: Ng
mesh_terms: D000818:Animals; D001596:Benzylamines; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007958:Leukocyte Count; D008168:Lung / Q000166:cytology*; D008252:Macaca fascicularis; D051379:Mice; D036641:Microscopy, Fluorescence, Multiphoton; D009113:Muramidase / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000166:cytology*; D011652:Pulmonary Circulation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins; D009113:Muramidase; C088327:plerixafor